Project Summary Schizophrenia is a severely debilitating psychiatric disorder that afflicts approximately 1% of the general population and is a serious public health problem with no cure. The major excitatory and inhibitory neurotransmitter systems, glutamate and GABA, are involved in the pathophysiology of schizophrenia. A better understanding of these systems could aid in the development of novel interventions for the treatment of schizophrenia and related disorders. The only noninvasive method that provides in vivo measurement of these chemicals is proton magnetic resonance spectroscopy (MRS), but accurate measurement at short echo times is problematic due to contaminating brain macromolecule signals. Although macromolecules are regarded as a nuisance signal in MRS research, they actually may be physiological meaningful. Brain macromolecules are higher in multiple sclerosis, stroke, brain tumors, and brain macromolecules increase in rodent models of brain inflammation. This R21 project addresses a major problem faced by MRS studies of schizophrenia, whether macromolecules are different in patients with schizophrenia. There are no investigations of brain macromolecules in schizophrenia. This project will investigate macromolecule differences in brain regions known to be involved in the pathophysiology of schizophrenia and that have shown MRS differences. The relationship between brain macromolecules and clinical and cognitive symptoms will also be investigated. The results of this project will generate a better understanding of the role of brain macromolecules in schizophrenia. If macromolecules are different between patients and controls, these measures may serve as biomarkers of the illness. This will provide impetus for a more definitive R01 study. If macromolecules are not different between patients and controls, this information is still very important and will provide the research community with confidence that MRS metabolite differences are not due to differences in macromolecule levels among groups. This project will also provide brain macromolecule spectra from multiple brain regions, all acquired from adults with schizophrenia to the research community to aid in spectral analysis.